Objectives/Specific Aims: The hypothesis of this proposal is that characterization of aberrantly methylated genes in esophageal cell lines and tissues will lead to a better understanding of the initiation and progression of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and has the promise to lead to the discovery of novel early-detection and/or prognostic markers for BE and EAC. The specific aims of this proposal are: 1) To identify novel methylated loci involved in the initiation and progression of BE through the use of microarrays, 2) To perform high-resolution methylation analysis of the CpG dinucleotides in candidate tumor suppressor genes, and 3) To identify and validate a panel of methylated genes that discriminates BE, BE with high-grade dysplasia, and EAC and predicts the progression from BE to EAC. Research Design: 1. cDNA expression and "methylation" arrays will be used to identify novel methylated genes in a unique panel of esophageal cell lines. 2. The pattern of CpG dinucleotide methylation will be analyzed in cell lines and primary tissues using MALDI-TOF technology. 3. A panel of candidate biomarkers will be tested in primary esophageal tissues, including normal esophagus, BE, BE with dysplasia, and cancer to determine their ability to discriminate between these histological tissue types. Candidate Career Goals and Career Development Plan: The candidate's goal is to become an academic physician-scientist performing translational research in the early-detection of cancer. The candidate's plan includes seeking out broad, interdisciplinary mentorship and enrolling in courses in biostatistics, bioinformatics, and clinical trial design to become a more complete and effective translational scientist. Relevance to Public Health: EAC is the most rapidly increasing cancer in the U.S., and most individuals diagnosed with EAC will never benefit from endoscopic screening. For this reason, a panel of novel DNA biomarkers promises to improve early-detection of BE or cancer and improve the dismal survival rate in patients diagnosed with esophageal adenocarcinoma.